tbuckley/cabot-search huggingface dataset:
HGG-41. Glioma oncogenesis in the constitutional mismatch repair deficiency (CMMRD) syndrome
Authors: Lea Guerrini-Rousseau, Jane Merlevede, Philippe Denizeau, Felipe Andrejuolo, Pascale Varlet, Stephanie Puget, Kevin Beccaria, Thomas Blauwblomme, Odile Cabaret, Nadim Hamzaoui, Franck Bourdeaut, Cecile Faure-Conter, Martine Muleris, Chrystelle Colas, Tiphaine Adam de Beaumais, David Castel, Etienne Rouleau, Laurence Brugieres, Jacques Grill, Marie-Anne Debily
Journal: Neuro-Oncology (2022)

Abstract PURPOSE: Constitutional Mismatch Repair Deficiency (CMMRD) is a cancer predisposition due to bi-allelic mutations in one of the four main mismatch repair (MMR) genes (PMS2, MSH2, MSH6 or MLH1) associated with early onset of cancers, especially glioblastomas (GBM). Our aim was to decipher the molecular specificities of gliomas occurring in this context. METHODS: A comprehensive analysis of clinical, histopathological and genomic data (whole exome sequencing) was performed for 12 children with a CMMRD for which we had available frozen brain tumor material (10 GBM and 2 anaplastic astrocytomas). RESULTS: Eight patients harbored an ultra-mutated phenotype with more than 100 somatic non synonymous (NS) SNV/Mb. No correlation was observed between the number of mutation and sex, age, overall survival or mutated MMR gene. POLE and POLD1 exonuclease domain driver somatic mutations were described for eight and one patients respectively. The 4/12 tumors without POLE somatic mutation did not show the classical ultra-hypermutation pattern. All patients with POLE mutation had already more than 20 NS SNV/Mb (median 40, [range 23-114]) suggesting that the hypermutation phenomenon started before the appearance of the somatic POLE mutation. The mutational signatures of the tumors, dominated by the MMR signatures, were not modified after the onset of the POLE mutation when analyzing the different mutation bursts. Specific recurrent somatic mutations were observed in SETD2 (9/12), TP53 (9/12), NF1 (9/12), EPHB2 (8/12), and DICER1 (7/12). Only half of the tumors overexpressed PDL1 by immunohistochemistry and this overexpression was not associated with a higher tumor mutation burden. CONCLUSION: CMMRD-associated gliomas have a specific oncogenesis that does not trigger usual pathways and mutations seen in sporadic pediatric or adult GBM. Frequent alterations in other pathways (e.g. MAPK or DNA-PK pathway) may suggests the use of other targeted therapies aside from PD1 inhibitors.
NFB-21. Neurofibromatosis Type I in the Setting of Neuro-Oncology
Authors: Molly Hemenway
Journal: Neuro-Oncology (2022)

Abstract Neurofibromatosis Type I (NF1) is an autosomal dominant genetic syndrome that is inherited or sporadic. Neuro-Oncology nurses are experienced in the multidisciplinary care of NF1 patients due to an increased incidence of brain tumors and the treatment of plexiform neurofibromas with Mek inhibitors. However, these children are also at higher risk of rare solid tumors, specifically malignant peripheral nerve sheath tumors (MPNST). Most brain tumors in NF1 have a good prognosis. Conversely, MPNST has an extremely poor prognosis. While patients with MPNST are often cared for by solid tumor care teams, the identification and diagnosis of the tumors occur under the care of the neuro-oncology care team. Complex care coordination for patients with NF1 and cancer is required. Specifically, patients with NF1 are more sensitive to chemotherapy, have a higher incidence of radiation-induced secondary tumors, and need monitoring for NF1 related health impacts. Nurses and nurse practitioners with expertise in neuro-oncology, NF1, and solid tumors must collaborate to provide comprehensive care. Teaching tools and clinical strategies have been developed to maintain patients’ continuity with the primary oncology team while gaining the support of subspecialists. The genetic basis, inheritance pattern, and characteristics of Neurofibromatosis Type I will be discussed as well as rare oncologic diagnoses that are more prevalent in children/young adults with NF1. The multidisciplinary approach to the care of the patient with NF1 and a rare cancer diagnoses at a tertiary care center as well as the optimization of care of patients with NF1 and other underlying syndromes and rare cancers will be reviewed. Increased knowledge of NF1 and the associated health impacts and risk of cancers will improve the care of all patients with NF1.
Exogenous Growth Differentiation Factor 15 (GDF15) exerts direct cardioprotective properties towards myocardial ischemia reperfusion injury
Authors: G Dogon, ER Rigal, LR Rochette, YB Bejot, CV Vergely
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Agence National de la Recherche (ANR) Introduction Growth differentiation factor 15 (GDF15) is a stress-responsive cytokine which can be produced under certain pathological situations, mainly related to inflammatory stress, aging and disease. While clinical data suggest that GDF15 is a powerful risk factor in several high cardiovascular risks situations such as myocardial infarction and coronary artery disease, experimental studies rather consider this cytokine as a cardioprotective molecule. Objective We therefore aimed to clarify the direct cardiac effects of GDF15 during ischemia-reperfusion (I-R) injury, at concentrations found in patients with high cardiovascular risk, such as these of patients presenting with acute myocardial infarction or stroke. Method In vivo ischemia reperfusion: Wistar male rats (200-340 g) were anesthetized with isoflurane and intubated before a left thoracotomy was performed between the 3rd and the 4th intercostal space. Rats were injected with either saline (Control groups) or 2.5 µg/kg of GDF15 (GDF15 groups), 20 minutes before the transient ligation of the left anterior descending artery for 30 min followed by 24h of reperfusion. Ex vivo ischemia reperfusion: Wistar male rats (250-400 g) were anesthetized with isoflurane before their hearts were isolated and perfused in a Langendorff model. Hearts were perfused either with saline (Control groups) or 2,000 ng/L of GDF15 upstream the coronary bed (GDF15 groups) for 10 minutes, then subjected to either 20 or 30 minutes of global normothermic total ischemia, followed by 2 h of reperfusion. Results GDF15 decreased the infarct size in vivo (42.4 ± 6 % vs. 65.3 ± 4.5 %, p&amp;lt;0.01) as well as in ex vivo (45.6 ± 3.8 % vs. 60.8 ± 3.8 %, p&amp;lt;0.05). Moreover, in our ex vivo model, GDF15 induced a better recovery of most contractile parameters after ischemia (higher left ventricular developed pressure, better heart rate recovery, better recovery in left ventricular contractility and relaxation, p&amp;lt;0.05 for all parameters). Conclusion These results demonstrate for the first time that exogenous preischemic short-term administration of GDF15 decreased cardiac cell death in vivo and also ex vivo, a situation where inflammatory, endocrine and nervous systems are not interfering. These original results suggest that GDF15 exerts direct cardioprotective properties towards ischemia-reperfusion injury. The molecular mechanisms have now to be investigated.
Adjuvant lenvatinib after radical resection in patients with hepatocellular carcinoma (HCC): Preliminary analysis of a prospective, multi-center, single-arm study.
Authors: Jian Zhou, Hui-Chuan Sun, Zhi-Yong Huang, Lianxin Liu, Tianfu Wen, Xiao-Dong Zhu, Yinghong SHI, Qiang Gao, Shuang-Jian Qiu, Zhenbin Ding, Zheng Wang, Qing-Hai Ye, Xiao-Wu Huang, Cheng Huang, Yuan-Fei Peng, Guoming Shi, Xiao-Ying Wang, Jia Fan
Journal: Journal of Clinical Oncology (2022)

e16158 Background: Chinese guidelines recommend surgical resection for patients with China Liver Cancer (CNLC) Stage Ia−IIIa HCC (equal to BCLC stage A/B and selected patients with BCLC stage C). Despite treatment, however, patients with CNLC stage IIb (tumor number &gt; 3) and IIIa (vascular invasion) disease have a high recurrence risk and poor overall survival (OS). Here we assessed the efficacy and safety of adjuvant lenvatinib in patients with high risk of disease recurrence. Methods: In this multi-center, single-arm, prospective clinical trial (NCT04227808), patients underwent radical (R0) resection for CNLC Stage IIb/IIIa HCC within 4-6 weeks were eligible and received treatment of lenvatinib (8 or 12 mg/day for body weight &lt; 60 and ≥60 kg, respectively. Dose modifications were permitted due to adverse reactions) until disease recurrence, intolerable toxicity or death. The primary endpoint was 1-year recurrence-free survival (RFS), and secondary endpoints included OS and safety. The total planned enrollment for this study is 50 patients and here we report our preliminary analysis results. Results: A total of 59 patients were screened from Mar 2020 to Dec 2021 and 50 were enrolled in the study. By the cut of date (Dec 31, 2021), 42 patients had at least one set of follow-up data and were included in the present analysis. The 42 patients were predominantly male (83.3%, n = 35), and the median age was 55.5 years (range: 26–73). 78.6% (n = 33) were HBV-positive and 21.4% (n = 9) of disease were non-viral. Five patients (11.9%) had CNLC Stage IIb and 37 (88.1%) had CNLC Stage IIIa HCC. The median duration of treatment was 8.4 months (range: 1.7-18.7) with a median follow-up of 11.3 months (95% CI: 6.6−15.9). 24% (n = 10) had experienced dose reduction or delay. The 1-year RFS rate was 50.5%, while the median RFS was 16.5 months (95% CI: 11.3–21.7). Two deaths occurred: one secondary to disease recurrence and one from hepatic encephalopathy without recurrence. In total, 90.5% (n = 38) of patients experienced ≥1 treatment-related adverse events (AE) of any grade, and five patients (11.9%) had grade 3 treatment-related AEs (thrombocytopenia in two cases, proteinuria in two cases, and elevated aspartate aminotransferase in one case). There was no treatment-related death. Conclusions: Adjuvant lenvatinib was well-tolerated in patients with CNLC Stage IIb/IIIa HCC after R0 resection. The median RFS was longer than our historical data (mRFS = 9.03 months), and these findings warrant further investigation in a controlled study. Funding: Eisai Co., Ltd. Clinical trial information: NCT04227808.
Clinical laboratory mutation analysis performed on aggressive B cell non-Hodgkin lymphoma patient biopsies.
Authors: Daniel J Landsburg, Gabriel C. Caponetti, Adam Bagg, Stephen J. Schuster, Sunita Nasta, James M. Gerson, Dale M. Frank, Stefan K. Barta, Jakub Svoboda, Siddharth Bhattacharyya, Julianne N Qualtieri, Megan S. Lim, Elise A. Chong, Jacquelyn Roth, Salvatore F. Priore, Safoora Deihimi, Jennifer J. Morrissette
Journal: Journal of Clinical Oncology (2022)

e19561 Background: Results from comprehensive genomic analysis performed on aggressive B cell non-Hodgkin lymphomas (aBNHL) patient (pt) biopsies (bx) have identified mutations (mut) which may be predictive of pt survival. However, results from mut analysis (MA) performed on aBNHL pt bx in clinical laboratories are not well-described. Methods: Bx diagnostic of non-Burkitt aBNHL obtained from 7/2015-2/2021 with MA performed in the Penn Center for Personalized Diagnostics clinical laboratory using 3 consecutive versions of lymphoma sequencing panels were retrospectively analyzed. Mut tested varied by panel. Mut detected with variant allele frequency (VAF) ≥10% were included. Results: MA was performed on 293 aBNHL pt bx with a successful assay for 270 (7.8% failure rate). Request for MA was made by interpreting hematopathologist 93% and treating clinician 7%. Median turnaround time (TAT) from receipt of bx to result report was 18 (range 8-53) days. Notable pt characteristics included prior/concurrent indolent lymphoma (IL) 31% and prior systemic therapy received for IL and/or aBNHL 38%. Notable bx characteristics included bx type paraffin-embedded tissue 85% and bone marrow 12%, histologic classification diffuse large B cell lymphoma 86% and high grade B cell lymphoma 13%, cell of origin (COO) by Hans algorithm non-germinal center B (non-GCB) 51% and GCB 44%, known double expressor lymphoma 30%, known MYC rearrangement 18%, known double hit lymphoma 9% and any mut detected with VAF ≥10% 82%. Number and percentage of mut occurring in ≥10% of bx (minimum tested bx for mut ≥92) with associated COO are listed in the table. Subset analysis of 147 bx obtained from pts with newly-diagnosed aBNHL (15% with previously-untreated IL) had similar bx characteristics to the entire population were analyzed for the presence of mut reported in poor-prognosis COO-associated classifications: Cluster 5 for non-GCB and Cluster 3 for GCB (PMID: 29713087), double-hit signature (DHITsig) for GCB (PMID: 30523716) and molecular high grade (MHG) for GCB (PMID: 30523719). For 77 non-GCB bx, 19% had Cluster 5 mut. For 59 GCB bx, 56% had at least one of Cluster 3, DHITsig or MHG mut. Conclusions: Clinical laboratory MA performed on nearly 300 aBNHL pt bx was highly successful with a short TAT and demonstrated recurrent gene mut associated with aBNHL development. In the subset of bx from previously-untreated pts, MA identified mut associated with poor-prognosis genetic subtypes of aBNHL.[Table: see text]
Phase 1 study of JNJ-69086420, an actinium-225-labeled antibody targeting human kallikrein-2, for advanced prostate cancer.
Authors: Michael J. Morris, A. Oliver Sartor, Jeffrey Y.C. Wong, Steven I Max, Hong Xie, Alex Yu, Chaitanya R. Divgi, Daniel Patricia, Anjali Narayan Avadhani, Neeta Pandit-Taskar, Pedro C. Barata, Luke T. Nordquist
Journal: Journal of Clinical Oncology (2022)

TPS5104 Background: Radioligand therapy for metastatic castration resistant prostate cancer (mCRPC) has been shown to prolong survival, delay disease progression, and improve quality of life, raising hopes that these gains will be amplified with even more cancer-specific targets and more powerful radioligands. Human kallikrein-related peptidase 2 (hK2) is a tumor-associated member of the kallikrein family that shares significant homology to prostate-specific antigen and is minimally expressed in normal non-prostate tissues. JNJ-69086420 (JNJ-420; 225 Ac-DOTA-h11B6 [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid]), is a first-in-class radioimmunotherapy targeted to hK2 antigen. In a phase 0 study of [ 111 In]-DOTA-h11B6, patients with mCRPC (progressed on standard therapies), treatment with a single dose of [ 111 In]-DOTA-h11B6 (2 mg) with/without 8 mg h11B6, demonstrated safety, good tumor localization, nominal normal-organ uptake, and no difference in pharmacokinetics (PK) between 2 and 10 mg antibody mass (Morris et al. J Clin Oncol. 2021 39:6 suppl, 122). We have initiated the first-in-human study to assess the safety, PK, pharmacodynamic (PD), and clinical activity of Ac-225 radiolabeled JNJ-420, to determine its recommended phase 2 dose (RP2D) in adults with advanced PC. Methods: This open-label, multicenter, phase 1 study will recruit approximately 50 men (aged ≥18 years) with advanced PC across dose escalation (Part 1) and expansion (Part 2) parts. Key eligibility criteria: mCRPC with histologic confirmation of adenocarcinoma, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, adequate organ function based on hematology and serum chemistry, and 1 or more prior novel androgen receptor-targeted therapies (prior chemotherapy acceptable). Key exclusion criteria: prior treatment with radium/strontium/samarium/radioconjugate therapy, superscan findings as protocol defined, active central nervous system metastases. In Part 1, men will receive intravenous (IV) injection of 50 μCi/ 2 mg JNJ-420 (once every 8 weeks) with one or multiple doses; escalation of dose levels to be based on dose limiting toxicities (DLTs) evaluation, until RP2D identification. In Part 2, JNJ-420 is to be given at one of the RP2D(s) determined in Part 1. Primary endpoint is safety (incidence and severity [grading per NCI-CTCAE V5.0] of AEs including DLTs). Secondary endpoints include prostate specific antigen response rate, overall response rate (PCWG3 modified RECIST 1.1 criteria), PK, PD, immunogenicity, and biomarker analyses. Enrollment began in Dec 2020; as of 10 Feb 2022, 4 sites have been initiated and 23 patients enrolled; currently, dose escalation is ongoing. Clinical trial information: NCT04644770.
External validation and comparison of two nomograms predicting the probability of lymph node involvement in patients subjected to robotic radical prostatectomy and concomitant lymph node dissection
Authors: N. Frego, M. Paciotti, P.P. Avolio, D. Maffei, R. Contieri, A. Uleri, M. Lazzeri, A. Saita, P. Casale, N.M. Buffi, G. Lughezzani
Journal: European Urology (2022)
Improving cryptococcal meningitis treatment in Africa
Authors: Munyaradzi Makoni
Journal: The Lancet Microbe (2022)

On Jan 17, 2022, a clinical trial started in Bloemfontein, South Africa that aimed to deliver an improved formulation of flucytosine—a lifesaving treatment for cryptococcal meningitis. In the same month, the South African Health Products Regulatory Authority made a landmark decision registering flucytosine in the country.
Implications of <sup>18</sup>F-FDG PET/CT findings before autologous stem cell transplant in patients with multiple myeloma.
Authors: Muhammad Azeem Khan, Danny Markabawi, Matthew Alberti, Jeffrey Burton, Ruby Maini, Vince Catalfamo, Ambuga Badari
Journal: Journal of Clinical Oncology (2022)

e20023 Background: The IMWG recommends using 18 F-FDG PET/CT (PET) to monitor response to therapy in multiple myeloma (MM). Prior studies in patients who received chemotherapy before autologous stem cell transplant (ASCT) found that severe FDG uptake on PET was associated with inferior event free survival. However, novel agents and monoclonal antibodies have changed the landscape of MM and chemotherapy is no longer used as initial treatment making the role of PET before ASCT unclear. This study explores findings on pre-ASCT PET that may predict shorter remissions after ASCT. Methods: This was a retrospective cohort study. Patients were included if they had a PET at least 60 days before ASCT between 2014 and 2021. All patients achieved at least a partial response (PR) prior to ASCT. The primary endpoint, PFS was defined as time to progression on labs, imaging or bone marrow biopsy necessitating change in therapy or resulting in death after ASCT. The cytogenetic risk category (CG), number of bone lesions at diagnosis, presence of severe FGD uptake on PET (defined as SUV max ≥ 4.2) and persistence of lesions on PET was recorded. Patients who did not experience the event of interest were censored at their last date of clinic follow up. Hazard ratios (HR) for disease progression were estimated using Cox proportional hazards models. Results: 151 patients were included in our study. All patients underwent induction with a 3-drug regimen containing a proteasome inhibitor (PI) and/or an immunomodulatory agent (IMiD). 32% had high risk CG, 44% had &gt; 3 bone lesions at diagnosis, 24% had severe FDG uptake and 29% had &gt; 3 lesions on pre-ASCT PET. The presence of high-risk CG [HR 2.08 (1.03 – 4.17)] and severe FDG uptake on diagnostic PET [HR 6.43 (2.58 – 16.07)] was associated with more aggressive disease and shorter PFS. Patients with &gt; 3 lesions in their pre-transplant PET had a statistically significant decreased PFS [HR 2.01 (1.02 – 3.96)] compared to those with ≤ 3 lesions. Conclusions: This study found that that persistence of &gt; 3 lesions on pre-ASCT PET were an adverse finding associated with an increased risk of progression. To our knowledge these findings have not previously been shown in patients treated with PIs and IMiDs before ASCT. Significantly shorter PFS was observed in patients with high-risk CG and severe FDG uptake on initial PET, consistent with our knowledge of MM. In addition to established risk factors for aggressive disease, persistence of &gt; 3 bone lesions on PET/CT could be used to identify a high-risk group of patients who may benefit from more intensive surveillance or therapy after ASCT. [Table: see text]
The development of systolic heart failure in case of pressure overload-induced left ventricular myocardial hypertrophy is associated with a unique microRNA expression profile in a rat model
Authors: M Ruppert, S Korkmaz-Icoz, B Agg, AA Sayour, A Olah, D Nagy, K Benke, P Ferdinandy, B Merkely, G Szabo, T Radovits
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): New National Excellence Program of the Ministry of Human Capacities Introduction Growing body of evidence suggests that distinct alterations in myocardial microRNA (miRNA) expression contribute to pressure overload (PO)-induced pathological cardiac remodeling. Nevertheless, it is still under intense investigation whether the changes in miRNA expression patterns are also associated with the decompensation of LV systolic function in case of PO-evoked LV hypertrophy (LVH). Hence, we aimed to characterize miRNA expression in PO-induced LVH with and without systolic heart failure (HF). Methods PO was evoked by abdominal aortic banding (AB) in male Sprague-Dawley rats. Age-matched, sham-operated animals served as controls. Functional and morphological alterations were assessed by echocardiography and histology. At the end of the experimental period, rats in the AB group were subcategorized based on ejection fraction [EF] into ABLVH (EF&amp;gt;40%) and ABHF groups (EF&amp;lt;40%). Global miRNA expression profiling was performed using next generation sequencing. Bioinformatics analysis was carried out to predict miRNA-target interactions. Expression of selected target genes was measured by qRT-PCR. Results Increased heart weight-to-tibial length, LV mass and fibrosis confirmed the development of pathological LVH in both the ABLVH and ABHF groups. Nevertheless, increased lung weight-to-tibial length, chamber dilatation and severely reduced EF was noted only in the ABHF and not in the ABLVH, when compared to the sham group. 50 miRNA showed different expression in the ABHF compared to the ABLVH group. Based on the altered gene expression profile, in silico bioinformatics analysis predicted several target genes. Among them, reduced mRNA expression level of Fmr1 (FMRP translational regulator 1), Zfpm2 (zinc finger protein, multitype 2), Wasl (WASP like actin nucleation promoting factor), Ets1 (ETS proto-oncogene 1) and Atg16l1 (Autophagy Related 16 Like 1) was confirmed in ABHF compared to ABLVH. Conclusions Decompensation of systolic function in PO-induced LVH is associated with unique miRNA profile leading to specific regulation of gene expression.